The present invention relates to a process for the preparation of non-hygroscopic salts of L(xe2x88x92)-carnitine. More precisely, the present invention relates to an improved process for the preparation of L(xe2x88x92)-carnitine acid fumarate (1:1) and of L(xe2x88x92)-carnitine L(+)-tartrate (2:1) by xe2x80x9chumid meltingxe2x80x9d, as it will be further specified in the following.
The high hygroscopicity of L(xe2x88x92)-carnitine inner salt recognizedly causes complex problems of processability, stability and storage both of the raw materials and of the finished products. For example, L(xe2x88x92)-carnitine inner salt tablets have to be packaged in blisters to prevent contact with the air, since, otherwise, even in the presence of normal humidity conditions, they would undergo alterations, swelling up and becoming pasty and sticky. However, the solid orally administrable compositions are the preferred presentation form, inasmuch as they make it particularly easy for users to take the substances and comply with optimum dosage regimens.
Up to now, the problem of L(xe2x88x92)-carnitine inner salt hygroscopicity has been approached by transforming it into salts with pharmacologically acceptable acids, provided these salts have the same therapeutical/nutritional activities of the inner salt and do not have unwanted toxic or side effects.
There is now an extensive body of literature, particularly patents, disclosing the production of stable, non-hygroscopic salts of L(xe2x88x92)-carnitine.
U.S. Pat. No. 4,602,039 (Sigma-Tau) discloses L(xe2x88x92)-carnitine acid fumarate (1:1) as a non-hygroscopic, pharmacologically acceptable L(xe2x88x92)-carnitine salt. EP 0,434,088 (Lonza) discloses the use of L(xe2x88x92)-carnitine tartrate (2:1), the preparation and physico-chemical characterization of which were, on the other hand, described by D.Muller and E.Strack in Hoppe Seyler""s Z.
Physiol. Chem. 353, 618-622, April 1972, for the preparation of solid forms suitable for the oral administration, such as tablets, capsules, powders or granulates, as said salts are capable of resisting at about 60% relative humidity.
The traditional processes for the industrial production of the two above mentioned salts (the only ones developed and marketed, up to now) have remarkable drawbacks in that they involve the use of large amounts of water or hydroalcoholic solutions in which L(xe2x88x92)-carnitine and the suitable acid are dissolved for carrying out the salification, and of organic solvents (such as methanol, ethanol and isobutanol) for the subsequent crystallization. For instance, according to the previously cited EP 0,434,088, L(xe2x88x92)-carnitine inner salt is added to a boiling solution of L(+)tartaric acid in aqueous 90% ethanol. This makes it necessary to concentrate large volumes of the solution containing the desired L(xe2x88x92)-carnitine at 50-60xc2x0 C. and under reduced pressure (about 200 Torr, 26664 Pa) for carrying out the crystallization, with remarkable energy waste and no quantitative yield.
In order to drastically reduce said energy waste and to avoid the use of organic solvents, WO 98/38157 discloses a process in which L(xe2x88x92)-carnitine inner salt is mixed at room temperature with the minimum amount of water necessary to obtain a slurry of semiliquid/pasty consistency which is added, at room temperature, with an equimolar amount of fumaric acid or one-half the equimolar amount of L(+)-tartaric acid with respect to L(xe2x88x92)-carnitine inner salt (in L(xe2x88x92)-carnitine acid fumarate the L(xe2x88x92)-carnitine/fumarate molar ratio is 1:1, whereas in L(xe2x88x92)-carnitine tartrate the L(xe2x88x92)-carnitine/tartrate molar ratio is 2:1). The above pasty mixture (containing 10 to 30% by weight of water) is blended at room temperature with formation of a solid mass consisting of the desired salt (100% yield) which is subsequently ground to the wanted particle size.
However, the absence of hygroscopicity and a suitable particle size distribution are not yet sufficient to provide an excellent processability of said compounds on standard devices for the preparation of finished pharmaceutical forms, in that the above processes do not always provide reproducible, steady and optimum density values of the products. It is in fact known that an inadequately low density (for example, for L(xe2x88x92)-carnitine acid fumarate, a tapped density value below 0.7 g/mL) provides a too light and flaky product which involves serious processability problems. The bulk density is not a reliable parameter for granulated or powdery products, in that even imperceptible perturbations of the test sample can give rise to remarkably different bulk density values. For the characterization of the density of said materials the tapped density is preferably used, which is the limit density obtained after tapping down the material by subjecting a graduated cylinder containing the granulate or powder to strokes, namely by hoisting the cylinder to a fixed height then dropping it for a fixed number of times.
The tapped density is usually determined according to the method described in U.S. Pharmacopoeia, National Formulary, Supplement, USP 23, NF 18, Nov. 15, 1997, pages 3976-3977. Said method is herein incorporated by reference.
The material is passed through a 1 mm (n. 18 mesh) sieve to crush any agglomerates formed during storage. About 100 g (M) of the test material are placed without tapping down in a 250 mL graduated cylinder.
Using a suitable device, the cylinder is hoisted then dropped under the action of its own weight, from a height of 14+2 mm, with a 300 times/minute fall frequency. The volume of the material after a first 500 fall cycle is then measured. After a second 750 fall cycle, the volume of material is measured again, and this is considered the final volume (Vf) if it does not differ from the first volume by more than 2%. Otherwise, one or more further 1250 fall cycles are carried out until the final volume does not differ from the previous value by more than 2%. The tapped density, in g/mL, is expressed by the formula: M/Vf.
Whereas the known processes do not provide granulates or powders of the above mentioned L(xe2x88x92)-carnitine salts, particularly of L(xe2x88x92)-carnitine acid fumarate, with tapped density values reproducible and suitable for a satisfactory processability in standard devices, the process of the present invention attains said object while overcoming other drawbacks, as it will be further described in details hereinbelow.
The process of the invention for the preparation of a stable, non-hygroscopic L(xe2x88x92)-carnitine salt selected from the group consisting of L(xe2x88x92)-carnitine acid fumarate (1:1) and L(xe2x88x92)-carnitine L(+)-tartrate (2:1), comprises:
(a) mixing at room temperature, in any desired order,
(1) L(xe2x88x92)-carnitine inner salt;
(2) fumaric acid or L(+)-tartaric acid, respectively in equimolar amount or in half the equimolar amount to L(xe2x88x92)-carnitine inner salt; and
(3) 5-9%, preferably 6-8%, by weight of water calculated on the weight of the (1)+(2)+(3) mixture;
(b) heating under stirring the above mixture at a temperature of 100-120xc2x0 C. to obtain a substantially colourless, transparent molten mass;
(c) cooling the molten mass until complete solidification; and
(d) grinding the solidified mass to obtain a granulate or powder having the desired particle size.
In step (a), water, in amount only 5-9%, preferably 6-8%, by weight calculated on the weight of the (1)+(2)+(3) mixture, cannot be considered either xe2x80x9cthe minimum amount of water necessary to obtain a mixture of semiliquid/pasty consistency xe2x80x9dof L(xe2x88x92)-carnitine inner salt and fumaric or L(+)-tartaric acid, according to the teachings of the above mentioned WO 98/38157 (in fact the mixture of step (a) is not in such form), or, even less, a solvent for said reagents. In the process according to the invention, water rather acts as an adjuvant for the subsequent melting step (b) which, due to the presence of water, takes place at a temperature (100-120xc2x0 C.) lower than the melting points of both the reagents and the final salts. The process of the present invention can therefore be defined as a xe2x80x9chumid melting processxe2x80x9d also considering the solidification pattern of the liquid (molten) mass of step (c) which solidifies as a glassy solid wherein, in the first solidification period, a number of crystallization seeds can be detected.
In step (c), xe2x80x9ccoolingxe2x80x9d means both simply promoting the cooling of the fluid mass, for example by pouring it onto a cold surface (even at room temperature) and inducing cooling (therefore accelerating it) by the use of suitable ventilation means or moving the fluid mass to a container equipped with a cooling jacket, as it is well known to those skilled in the art.
The xe2x80x9ccomplete solidificationxe2x80x9d can be the direct result of the above defined cooling (promoted or accelerated) or be induced (and then further accelerated compared with the simple cooling procedure) by adding a crystallization initiator to the still fluid mass. Preferably 1-2% by weight on the weight of the stirred mass of a fine powder of L(xe2x88x92)-carnitine acid fumarate (1:1) or of L(xe2x88x92)-carnitine L(+)-tartrate (2:1) is added, respectively. The addition is preferably carried out when the temperature of the cooling mass is about 60-90xc2x0 C. operating according to the two different procedures mentioned above, the duration of the solidification step can be suitably varied from about 60 minutes (with no crystallization initiator) to about 1-5 minutes.
The grinding step (d) can be carried out in a single operation or in two sub-steps, (d.1) and (d.2): in (d.1) a first coarse grinding is effect to promote drying of the solidified mass (which takes place very quickly by keeping the resulting granulate at 50-60xc2x0 C. under vacuum); in (d.2) grinding of the dried product is continued until the desired particle size is achieved.
Operation according to the processes known in art could never provide granulates or powders of L(xe2x88x92)-carnitine acid fumarate having tapped density of at least 0.8 g/mL, therefore the present invention further relates to such granulates or powders as novel products. Preferably, the tapped density thereof is 0.82-0.86 g/mL. Said tapped density values, which are always reproducible when obtained by the process of the invention, are optimum to provide an excellent processability of the relevant granulate or powder.